Cumulative Index

Diffuse liver disease is a growing problem and a major cause of death worldwide. In the final stages the treatment often involves liver resection or transplant and in deciding what course of action is to be taken it is crucial to have a correct assessment of the function of the liver. The current “gold standard” for this assessment is to take a liver biopsy which has a number of disadvantages. As an alternative, a method involving magnetic resonance imaging and mechanistic modeling of the liver has been developed at Linköping University. One of the obstacles for this method to overcome in order to reach clinical implementation is the speed of the parameter estimation. In this project the methodology of metamodeling is tested as a possible solution to this speed problem. Metamodeling involve making models of models using extensive model simulations and mathematical tools. With the use of regression methods, clustering algorithms, and optimization, different methods for parameter estimation have been evaluated. The results show that several, but not all, of the parameters could be accurately estimated using metamodeling and that metamodeling could be a highly useful tool when modeling biological systems. With further development, metamodeling could bring this non-invasive method for estimation of liver function a major step closer to application in the clinic

Metamodeling for ultra-fast parameter estimation : Theory and evaluation of use in real-time diagnosis of diffuse liver disease

Diffuse liver disease is a growing problem and a major cause of death worldwide. In the final stages the treatment often involves liver resection or transplant and in deciding what course of action is to be taken it is crucial to have a correct assessment of the function of the liver. The current “gold standard” for this assessment is to take a liver biopsy which has a number of disadvantages. As an alternative, a method involving magnetic resonance imaging and mechanistic modeling of the liver has been developed at Linköping University. One of the obstacles for this method to overcome in order to reach clinical implementation is the speed of the parameter estimation. In this project the methodology of metamodeling is tested as a possible solution to this speed problem. Metamodeling involve making models of models using extensive model simulations and mathematical tools. With the use of regression methods, clustering algorithms, and optimization, different methods for parameter estimation have been evaluated. The results show that several, but not all, of the parameters could be accurately estimated using metamodeling and that metamodeling could be a highly useful tool when modeling biological systems. With further development, metamodeling could bring this non-invasive method for estimation of liver function a major step closer to application in the clinic

Quantification of nuclear transport in single cells

Regulation of nuclear transport is a key cellular function involved in many central processes, such as gene expression regulation and signal transduction. Rates of protein movement between cellular compartments can be measured by FRAP. However, no standard and reliable methods to calculate transport rates exist. Here we introduce a method to extract import and export rates, suitable for noisy single cell data. This method consists of microscope procedures, routines for data processing, an ODE model to fit to the data, and algorithms for parameter optimization and error estimation. Using this method, we successfully measured import and export rates in individual yeast. For YFP, average transport rates were 0.15 sec-1. We estimated confidence intervals for these parameters through likelihood profile analysis. We found large cell-to-cell variation (CV = 0.79) in these rates, suggesting a hitherto unknown source of cellular heterogeneity. Given the passive nature of YFP diffusion, we attribute this variation to large differences among cells in the number or quality of nuclear pores. Owing to its broad applicability and sensitivity, this method will allow deeper mechanistic insight into nuclear transport processes and into the largely unstudied cell-to-cell variation in kinetic rates.Article id 001768.</p

The interactions between soil-biosphere-atmosphere (ISBA) land surface model multi-energy balance (MEB) option in SURFEXv8-Part 2 : Introduction of a litter formulation and model evaluation for local-scale forest sites

Land surface models (LSMs) need to balance a complicated trade-off between computational cost and complexity in order to adequately represent the exchanges of energy, water and matter with the atmosphere and the ocean. Some current generation LSMs use a simplified or composite canopy approach that generates recurrent errors in simulated soil temperature and turbulent fluxes. In response to these issues, a new version of the interactions between soil-biosphere-atmosphere (ISBA) land surface model has recently been developed that explicitly solves the transfer of energy and water from the upper canopy and the forest floor, which is characterized as a litter layer. The multi-energy balance (MEB) version of ISBA is first evaluated for three well-instrumented contrasting local-scale sites, and sensitivity tests are performed to explore the behavior of new model parameters. Second, ISBA-MEB is benchmarked against observations from 42 forested sites from the global micrometeorological network (FLUXNET) for multiple annual cycles. It is shown that ISBA-MEB outperforms the composite version of ISBA in improving the representation of soil temperature, ground, sensible and, to a lesser extent, latent heat fluxes. Both versions of ISBA give comparable results in terms of simulated latent heat flux because of the similar formulations of the water uptake and the stomatal resistance. However, MEB produces a better agreement with the observations of sensible heat flux than the previous version of ISBA for 87.5% of the simulated years across the 42 forested FLUXNET sites. Most of this improvement arises owing to the improved simulation of the ground conduction flux, which is greatly improved using MEB, especially owing to the forest litter parameterization. It is also shown that certain processes are also modeled more realistically (such as the partitioning of evapotranspiration into transpiration and ground evaporation), even if certain statistical performances are neutral. The analyses demonstrate that the shading effect of the vegetation, the explicit treatment of turbulent transfer for the canopy and ground, and the insulating thermal and hydrological effects of the forest floor litter turn out to be essential for simulating the exchange of energy, water and matter across a large range of forest types and climates